N-biarylamides

ABSTRACT

The invention relates to N-biarylamides, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improvement in cognition, concentration power, learning power and/or memory.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/235,743, filed Sep. 19, 2011, which application is a continuation ofU.S. patent application Ser. No. 12/099,108, filed on Apr. 7, 2008, (nowU.S. Pat. No. 8,030,329, issued October 4, 2011), which is a divisionalapplication of U.S. patent application Ser. No. 10/565,181, filed onOct. 16, 2006, (now U.S. Pat. No. 7,354,930, issued Apr. 8, 2008), whichwas filed under 35 U.S.C. §371 as a National Phase Application ofInternational Application No. PCT/EP2004/008037, filed Jul. 19, 2004,which application claims priority to German Patent Application SerialNo. 103 34 724.0, filed Jul. 30, 2003, the contents of each of which areincorporated herein by reference in their entireties.

The invention relates to N-biarylamides, to a process for thepreparation thereof and to the use thereof for producing medicaments forthe treatment and/or prophylaxis of diseases and for improvingperception, concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34,563-582). A functional nAChR consists of five subunits which may bedifferent (certain combinations of α1-9 and β1-4,γ,δ,ε subunits) oridentical (α7-9). This leads to the formation of a diversity of subtypeswhich differ in the distribution in the muscles, the nervous system andother organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have the corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylcholine receptors areinvolved in learning and memory processes (e.g. Rezvani and Levin, Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (α7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

Certain quinuclidinecarboxanilides are described as antiarrhythmics andlocal anesthetics (cf., for example, FR 1.566.045, GB 1 578 421 andOppenheimer et al. Life Sci. 1991, 48, 977-985).

WO 01/60821 discloses biarylcarboxamides with affinity for the α7 nAChRfor the treatment of learning and perception impairments.

WO 03/043991, WO 93/055878 and WO 04/013136 disclose quinuclidinaminederivatives and WO 03/051874, WO 03/078431 and DE 10162442.5 disclosequinuclidine acid derivatives which are suitable as α7-nAChR agonistsfor the treatment of learning and perception impairments.

The present invention relates to compounds of the formula

in which

-   R¹ is a group of the formula —NR²—CO—NR³R⁴, —NR²—CO—CO—OR⁵,    —NH—SO₂R⁶, —SO₂NHR⁷ or —NH—CO—R⁸, where    -   R² is hydrogen or C₁-C₆-alkyl,    -   R³ and R⁴ are independently of one another hydrogen,        C₁-C₆-alkyl, C₃-C₈-cycloalkyl or phenyl, which is optionally        substituted by up to 3 radicals independently of one another        selected from the group of halogen, cyano, C₁-C₆-alkyl,        C₁-C₆-alkoxy, trifluoromethyl and trifluoromethoxy, or    -   R³ and R⁴ together with the nitrogen atom to which they are        bonded form a 5- to 6-membered heterocyclyl,    -   R⁵ is hydrogen, C₁-C₆-alkyl, C₃-C₈-cycloalkyl or aryl, where        C₁-C₆-alkyl is optionally substituted by aryl,    -   R⁶ is C₁-C₆-alkyl, C₃-C₈-cycloalkyl, 5- to 6-membered        heterocyclyl, aryl or 5- to 6-membered heteroaryl, where        C₁-C₆-alkyl is optionally substituted by aryl,    -   R⁷ is hydrogen, C₁-C₆-alkyl, C₃-C₈-cycloalkyl, 5- to 6-membered        heterocyclyl, aryl or 5- to 6-membered heteroaryl, where        C₁-C₆-alkyl is optionally substituted by aryl,    -   R⁸ is C₃-C₈-cycloalkyl, C₁-C₆-alkyl or phenyl, where C₁-C₆-alkyl        is substituted by C₁-C₆-alkoxy and phenyl by 1 to 3 radicals        independently of one another selected from the group of halogen,        cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, trifluoromethyl and        trifluoromethoxy,        and the salts, solvates and solvates of the salts thereof.

Compounds of the invention are the compounds of the formula (I) and thesalts, solvates and solvates of the salts thereof; the compounds whichare encompassed by formula (I) and have the formulae mentionedhereinafter and the salts, solvates and solvates of the salts thereof,and the compounds which are encompassed by formula (I) and are mentionedhereinafter as exemplary embodiments and the salts, solvates andsolvates of the salts thereof, where the compounds which are encompassedby formula (I) and are mentioned hereinafter are not already salts,solvates and solvates of the salts.

The compounds of the invention may, depending on their structure, existin stereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and respectivemixtures thereof. The stereoisomerically pure constituents can beisolated in a known manner from such mixtures of enantiomers and/ordiastereomers.

The compounds of the invention may also be in the form of the salts,solvates or solvates of the salts thereof.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention maybe acid addition salts of the compounds with mineral acids, carboxylicacids or sulfonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acidor benzoic acid.

However, salts which may be mentioned are also salts with conventionalbases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts derived from ammonia or organic amines such as,for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine,1-ephenamine or methylpiperidine.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds which form a complex with solvent molecules bycoordination in the solid or liquid state. Hydrates are a special formof solvates in which the coordination takes place with water.

In addition, the present invention also encompasses prodrugs of thecompounds of the invention. The term “prodrugs” encompasses compoundswhich themselves may be biologically active or inactive but areconverted (for example by metabolism or hydrolysis) to compounds of theinvention during their residence time in the body.

For the purposes of the present invention, the substituents generallyhave the following meaning:

Aryl stands for naphthyl or phenyl, preferably phenyl.

C₁-C₆- and C₁-C₄-alkoxy stands for a straight-chain or branched alkoxyradical respectively having 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkoxy radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. The following maybe mentioned by way of example and preferably: methoxy, ethoxy,n-propoxy, isopropoxy, tert.butoxy, n-pentoxy and n-hexoxy.

C₁-C₆- and C₁-C₄-alkyl stand for a straight-chain or branched alkylradical respectively having 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkyl radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. The following maybe mentioned by way of example and preferably: methyl, ethyl, n-propyl,isopropyl, tert.butyl, n-pentyl and n-hexyl.

C₃-C₈-, C₃-C₆- and C₅-C₆-cycloalkyl stand for cyclopropyl, cyclopentyl,cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Those which may bementioned preferably are cyclopropyl, cyclopentyl and cyclohexyl andparticularly preferably are cyclopentyl and cyclohexyl.

Halogen stands for fluorine, chlorine, bromine or iodine. Fluorine,chlorine and bromine are preferred. Fluorine and chlorine areparticularly preferred.

5- to 6-membered heteroaryl stands for an aromatic radical having 5 to 6ring atoms and up to 4, preferably up to 2, heteroatoms from the seriesS, O and/or N. The heteroaryl radical may be bonded via a carbon atom orheteroatom. The following may be mentioned by way of example andpreferably: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,pyridyl, pyrimidinyl and pyridazinyl.

5- to 6-membered heterocclyl stands for a heterocyclic radical having 5to 6 ring atoms and up to 3, preferably 2, heteroatoms or hetero groupsfrom the series N, O, S, SO, SO₂, with preference for N and O. Theheterocyclyl radicals may be saturated or partially unsaturated.Saturated heterocyclyl radicals are preferred. The heterocyclyl radicalsmay be bonded via a carbon atom or a heteroatom. The following may bementioned by way of example and preferably: pyrrolinyl,tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, piperazinyl,thiopyranyl, morpholinyl.

When radicals in the compounds of the invention are optionallvsubstituted, unless otherwise specified the radicals may have one ormore identical or different substituents. Substitution by up to threeidentical or different substituents is preferred.

Preference is given to compounds of the formula (I)

in which

-   R¹ is a group of the formula —NR²—CO—NR³R⁴, —NR²—CO—CO—OR⁵,    —NH—SO₂R⁶, —SO₂NHR⁷ or —NH—CO—R⁸, where    -   R² is hydrogen or C₁-C₄-alkyl,    -   R³ and R⁴ are independently of one another hydrogen,        C₁-C₄-alkyl, C₃-C₆-cycloalkyl or phenyl, which is optionally        substituted by up to 2 radicals independently of one another        selected from the group of fluorine, chlorine, bromine, cyano,        C₁-C₄-alkyl, C₁-C₄-alkoxy, trifluoromethyl and trifluoromethoxy,        or    -   R³ and R⁴ together with the nitrogen atom to which they are        bonded form a 5- to 6-membered heterocyclyl,    -   R⁵ is hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, or aryl, where        C₁-C₄-alkyl is optionally substituted by aryl,    -   R⁶ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, 5- to 6-membered        heterocyclyl, aryl or 5- to 6-membered heteroaryl, where        C₁-C₄-alkyl is optionally substituted by aryl,    -   R⁷ is hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, 5- to 6-membered        heterocyclyl, aryl or 5- to 6-membered heteroaryl, where        C₁-C₄-alkyl is optionally substituted by aryl,    -   R⁸ is C₃-C₆-cycloalkyl, C₁-C₄-alkyl or phenyl, where C₁-C₄-alkyl        is substituted by C₁-C₄-alkoxy and phenyl by 1 to 2 radicals        independently of one another selected from the group of        fluorine, chlorine, bromine, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,        trifluoromethyl and trifluoromethoxy,        and the salts, solvates and solvates of the salts thereof.

Preference is likewise given to compounds of the formula (I) in which

-   R¹ is a group of the formula —NH—CO—NHR³, NH—CO—CO—OH, —NH—SO₂R⁶,    —SO₂NHR⁷ or —NH—CO—R⁸, where    -   R³ is hydrogen, C₁-C₄-alkyl, C₅-C₆-cycloalkyl or phenyl, which        is optionally substituted by C₁-C₄-alkoxy,    -   R⁶ is C₁-C₄-alkyl or phenyl, where C₁-C₄-alkyl is optionally        substituted by phenyl,    -   R⁷ is hydrogen or C₁-C₄-alkyl which is optionally substituted by        phenyl,    -   R⁸ is C₅-C₆-cycloalkyl, methoxymethyl or phenyl which is        substituted by fluorine or chlorine,        and the salts, solvates and solvates of the salts thereof.

Preference is likewise given to compounds of the formula

in which R¹ has the meanings indicated above, and the salts, solvatesand solvates of the salts thereof.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention further relates to a process for preparing the compoundsof the invention, characterized in that

[A] compounds of the formula

-   -   in which    -   X is hydroxy or a suitable leaving group such as, for example,        chlorine or pentafluorophenoxy,    -   are reacted with a compound of the formula

-   -   in which    -   R¹ has the abovementioned meanings,    -   in an inert solvent, where appropriate in the presence of a        condensing agent and where appropriate in the presence of a        base,        or

[B] compounds of the formula (II) initially are reacted with a compoundof the formula

-   -   in which    -   Y is a suitable leaving group such as, for example, triflate or        halogen, preferably bromine or iodine,    -   where appropriate in an inert solvent, where appropriate in the        presence of a condensing agent and where appropriate in the        presence of a base to give compounds of the formula

-   -   in which    -   Y has the abovementioned meanings,    -   and the latter are then reacted in a coupling reaction with        compounds of the formula

-   -   in which R¹ has the abovementioned meanings, and    -   R⁹ is hydrogen or methyl, or the two radicals together form a        CH₂CH₂ or C(CH₃)₂—C(CH₃)₂ bridge,    -   in an inert solvent in the presence of a suitable catalyst and        in the presence of a base,        and the resulting compounds of the invention are reacted where        appropriate with the appropriate (i) solvents and/or (ii) bases        or acids to give the solvates, salts and/or solvates of the        salts thereof.

If X is a leaving group, preference is given to chlorine, mesyloxy andisobutyloxycarbonyloxy, in particular chlorine.

Examples of inert solvents for process steps (II)+(III)→(I) and(II)+(IV)→(V) are halohydrocarbons such as methylene chloride,trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide,acetonitrile or pyridine. Dimethylformamide, tetrahydrofuran methylenechloride, or chloroform is preferred.

Condensing agents for process steps (II)+(III)→(I) and (II)+(IV)→(V)are, for example, carbodiimides such as, for example, N,N′-diethyl-,N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide)or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoliumcompounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxy-tri(dimethyl-amino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures thereof.

It may be advantageous where appropriate to use these condensing agentsin the presence of an auxiliary nucleophile such as, for example,1-hydroxybenzotriazole (HOBt).

HATU or the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and 1-hydroxybenzotriazole (HOBt) in dimethylformamide is particularlypreferred.

Examples of bases for process steps (II)+(III)→(I) and (II)+(IV)→(V) arealkali metal carbonates such as, for example, sodium or potassiumcarbonate or bicarbonate, or organic bases such as trialkylamines, e.g.triethylamine, or N-methylmorpholine, N-methylpiperidine,4-dimethylaminopyridine or diisopropylethylamine.

Process steps (II)+(III)→(I) and (II)+(IV)→(V) are preferably carriedout in a temperature range from room temperature to 50° C. underatmospheric pressure.

Examples of inert solvents for process step (V)+(VI)→(I) are ethers suchas dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such asbenzene, xylene or toluene, or other solvents such as nitrobenzene,dimethylformamide, dimethylacetamide, dimethyl sulfoxide orN-methylpyrrolidone. Solvents such as, for example, dimethylformamide,dimethylacetamide, dimethyl sulfoxide or 1,2-dimethoxyethane arepreferred.

Catalysts suitable for process step (V)+(VI)→(I) are for examplepalladium catalysts usual for Suzuki couplings, with preference forcatalysts such as, for example,dichlorobis(triphenylphosphine)palladium,tetrakistriphenylphosphine-palladium, palladium(II) acetate orbis(diphenylphosphino)ferrocenepalladium(II) chloride (cf., for example,e.g. A. Suzuki, Acc. Chem. Res. 1982, 15, 178ff; Miyaura et al., J. Am.Chem. Soc. 1989, 111, 314).

Bases suitable for process step (V)+(VI)→(I) are for example potassiumacetate, cesium, potassium or sodium carbonate, barium hydroxide,potassium tert-butoxide, cesium fluoride or potassium phosphate. Cesiumcarbonate or sodium carbonate is preferred.

Process step (V)+(VI)→(I) is preferably carried out in a temperaturerange from room temperature to 130° C. under atmospheric pressure.

The compounds of the general formulae (II) and (VI) are known or can besynthesized by known processes from the appropriate precursors [cf., forexample, for compounds of the general formula (II): Kato et al., Chem.Pharm. Bull. 1995, 43, 1351-1357; Orlek et al., J. Med. Chem. 1991, 34,2726-2735; Plate et al., Bioorg. Med. Chem. 2000, 8, 449-454; forcompounds of the general formula (VI): D. S. Matteson, in:Stereodirected Synthesis with Organoboranes, edited by K. Hafner, C. W.Rees, B. M. Trost, J.-M. Lehn, P. v. Ragué Schleyer, Springer-Verlag,Heidelberg 1995; H. C. Brown, G. W. Kramer, A. B. Levy, M. M. Midland,Organic Synthesis via Boranes, Wiley, New York 1975; A. Pelter, K.Smith, H. C. Brown, Borane Reagents, Academic Press, London 1988].

Compounds of the formulae (III) and (IV) are likewise known or can besynthesized by known processes from the appropriate precursors (cf., forexample, Comprehensive Heterocyclic Chemistry, Katritzky et al.,editors, Elsevier, 1996). Thus, for example, benzoic acid derivativescan be converted as shown in the following synthesis scheme byrearrangement (Curtius degradation) of the corresponding carbonyl azidesinto the corresponding aniline derivatives (cf., for example, S.Deprets, G. Kirsch, Eur. J. Org. Chem. 2000, 7, 1353ff):

The compounds of the invention are suitable for use as medicaments forthe treatment and/or prophylaxis of diseases in humans and/or animals.

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted.

They are notable as ligands, especially agonists, on the α7 nAChR.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other medicamentsfor the treatment and/or prevention of cognitive impairments, especiallyof Alzheimer's disease. Because of their selective effect as α7 nAChRagonists, the compounds of the invention are particularly suitable forimproving perception, concentration, learning or memory, especiallyafter cognitive impairments like those occurring for example insituations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memoryloss, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post-stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, attentiondeficit hyperactivity disorder, Alzheimer's disease, Lewy body dementia,dementia with degeneration of the frontal lobes, including Pick'ssyndrome, Parkinson's disease, progressive nuclear palsy, dementia withcorticobasal degeneration, amyotrophic lateral sclerosis (ALS),Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, schizophrenia, schizophreniawith dementia or Korsakoff's psychosis.

The present invention further relates to a method for the treatmentand/or prophylaxis of disorders, in particular the aforementioneddisorders, by use of an effective amount of the compounds of theinvention.

The compounds of the invention can be employed alone or in combinationwith other active ingredients for the prevention and treatment of thesequelae of neurodegenerative disorders. Preferred examples which may bementioned of neurodegenerative disorders are Alzheimer's disease andParkinson's disease.

The compounds of the invention can be employed alone or in combinationwith other medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994),especially for the treatment of cancer-induced pain and chronicneuropathic pain like, for example, that associated with diabeticneuropathy, postherpetic neuralgia, peripheral nerve damage, centralpain (for example as a consequence of cerebral ischemia) and trigeminalneuralgia, and other chronic pain such as, for example, lumbago,backache (low back pain) or rheumatic pain. In addition, these activeingredients are also suitable for the therapy of primary acute pain ofany origin and of secondary states of pain resulting therefrom, and forthe therapy of states of pain which were formerly acute and have becomechronic.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7 nAChR byInhibition of [³H]-Methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. (Neuropharmacol. 1999, 38, 679-690).

Rat brain tissue (hippocampus or whole brain) is homogenized inhomogenization buffer (10% w/v) (0.32 M sucrose, 1 mM EDTA, 0.1 mMphenylmethylsulfonyl fluoride (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.)at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 min). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). This pellet is referred to as the P2 fraction.

The P2 pellet is washed twice with binding buffer (50 mM Tris-HCl, 1 mMMgCl₂, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4), and centrifuged (15000×g, 4° C., 30 min).

The P2 membranes are resuspended in binding buffer and incubated in avolume of 250 μl (amount of membrane protein 0.1-0.5 mg) in the presenceof 1-5 nM [³H]-methyllycaconitine, 0.1% (w/v) BSA (bovine serum albumin)and various concentrations of the test substance at 21° C. for 2.5 h.The non-specific binding is determined by incubation in the presence of1 μM-bungarotoxin or 100 μM nicotine or 10 μM MLA (methyllycaconitine).

The incubation is stopped by adding 4 ml of PBS (20 mM Na₂HPO₄, 5 mMKH₂PO₄, 150 mM NaCl, pH 7.4, 4° C.) and filtering through type A/B glassfiber filters (Gelman Sciences) which have previously been placed in0.3% (v/v) polyethyleneimine (PEI) for 3 h. The filters are washed twicewith 4 ml of PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant K_(i) of the test substance was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor are displaced), thedissociation constant K_(D) and the concentration L of[³H]methyllycaconitine (K_(i)=IC₅₀/(1+L/K_(D))).

In place of [³H]-methyllycaconitine it is also possible to employ otherα7 nAChR-selective radioligands such as, for example,[¹²⁵I]-α-bungarotoxin or nonselective nAChR radioligands together withinhibitors of other nAChRs.

Representative in vitro data for the effects of the compounds of theinvention are shown in Table A:

TABLE A Example no. K_(i) [nM] 2 2 5 <1 7 <1 11 16 15 27

The suitability of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

2. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is carried out as described by Blokland et al., NeuroReport1998, 9, 4205-4208; A. Ennaceur, J. Delacour, Behav. Brain Res. 1988,31, 47-59; A. Ennaceur, K. Meliani., Psychopharmacology 1992, 109,321-330; and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject, it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning- and memory-improving effect will lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they wereunfamiliar and new. A discrimination index greater than zero means thatthe rat inspects the new object longer than the old one; that is to saythe rat has recognized the old object.

3. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the totaltime for which the adult animal investigates the juvenile animal ismeasured for 2 minutes (trial 1). All behaviors clearly directed at theyoung animal are measured, i.e. anogenital inspection, pursuit andgrooming, during which the old animal is no further than 1 cm from theyoung animal. The juvenile animal is then taken out, and the adult isleft in its test cage (for 24-hour retention, the animal is returned toits home cage). The test animal is treated with substance before orafter the first test. Depending on the timing of the treatment, thelearning or the storage of the information about the young animal can beinfluenced by the substance. After a fixed period (retention), the testis repeated (trial 2). A larger difference between the investigationtimes measured in trials 1 and 2 means that the adult animal hasremembered the young animal better.

The compounds of the invention are suitable for use as medicaments forhumans and animals.

The present invention also includes pharmaceutical preparations which,besides inert, nontoxic, pharmaceutically suitable excipients andcarriers, contain one or more compounds of the invention, or whichconsist of one or more compounds of the invention, and to processes forproducing these preparations.

The compounds of the invention are to be present in these preparationsin a concentration of from 0.1 to 99.5% by weight, preferably from 0.5to 95% by weight, of the complete mixture.

Besides the compounds of the invention, the pharmaceutical preparationsmay also contain other active pharmaceutical ingredients.

The abovementioned pharmaceutical preparations can be produced by knownmethods in a conventional way, for example using the excipient(s) orcarrier(s).

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to reach the stated doserange.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible for example when wateris used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behavior towards themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

ABBREVIATIONS

-   conc. concentrated-   DAD diode array detector-   DCI direct chemical ionization (in MS)-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   ESI electrospray ionization (in MS)-   h hour(s)-   HPLC high pressure/high performance liquid chromatography-   LC-MS coupled liquid chromatography-mass spectroscopy-   min. minute(s)-   MS mass spectroscopy-   NMR nuclear magnetic resonance spectroscopy-   PBS phosphate buffered saline-   PdCl₂(dppf) bis(diphenylphosphaneferrocenyl)palladium(II) chloride-   RT room temperature (20° C.)-   R_(f) retention time (in HPLC)    HPLC and LC-MS Methods:    Method 1:

Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm×2mm, 3.5 μm; eluent A: 5 ml HClO4/L H₂O, eluent B: acetonitrile;gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; flowrate: 0.75 ml/min; temperature: 30° C.; UV detection: 210 nm.

Method 2:

MS instrument type: Micromass ZQ; HPLC instrument type: Water Alliance2790; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; eluent B:acetonitrile+0.05% formic acid; eluent A: water+0.05% formic acid;gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min 90% B→+5.5 min 90% B; oven:45° C.; flow rate: 0.0 min 0.75 ml/min→4.5 min 0.75 m/min→5.5 min 1.25ml/min; UV detection: 210 nm.

Method 3:

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 series;UV DAD; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; eluent A:water+500 μl of 50% formic acid/L, eluent B: acetonitrile+500 μl of 50%formic acid/L; gradient: 0.0 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5min 90% B; oven: 50° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.

STARTING COMPOUNDS EXAMPLE 1A(rac)-1-Azabicyclo[2.2.2]octane-3-carbonitrile

20.4 g (163 mmol) of 3-quinuclidinone and 41.4 g (212 mmol) of(4-toluenesulfonyl)methyl isocyanide are introduced into 435 ml of1,2-dimethoxyethane and 16 ml of dry ethanol while cooling in ice. 45.7g (407 mmol) of potassium tert-butoxide are slowly added in such a waythat the temperature does not rise above 10° C. The mixture is thenheated at 40° C. for 2.5 h. After cooling to RT, the resulting solid isfiltered off. The filtrate is concentrated and chromatographed onneutral alumina (mobile phase: dichloromethane→ethyl acetate→ethylacetate/methanol 50:1). 22.9 g (quant.) of the racemic product areobtained in slightly impure form.

EXAMPLE 2A (R)-1-Azabicyclo[2.2.2]octane-3-carbonitrile

Enantiomer separation of the racemate from Example 1A takes place byHPLC on a chiral phase; [column: Daicel Chiralpak AD 250 mm×20 mm;eluent: 5% water, 87% acetonitrile, 8% acetonitrile with 2%diethylamine; flow rate: 10 ml/min; detection: 220 nm; volume injected:0.3 ml]. 8.7 g of the title compound (87% of theory) are isolated fromthe separation of 20 g of racemic1-azabicyclo[2.2.2]octane-3-carbonitrile.

R_(t)=6.19 min [Chiralpak AD 250 mm×4.6 mm, 10 μm; eluent: 5% water, 95%acetonitrile with 2% diethylamine; temperature: 30° C.; flow rate: 1.0ml/min].

EXAMPLE 3A (R)-1-Azabicyclo[2.2.2]octane-3-carboxylic acid

7.50 g (55.1 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carbonitrile(Example 2A) are heated together with 78 ml of conc. hydrochloric acidunder reflux for 4 h. The solvent is removed under reduced pressure, andremaining water is removed by distillation with toluene several times.12.9 g of the title substance, which still contains inorganic salts, areobtained and reacted without further purification.

EXAMPLE 4A(3R)—N-(4-Bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide

9.17 g (47.8 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid(Example 3A) are heated together with 160 ml of thionyl chloride underreflux for 1 h. Excess thionyl chloride is removed under reducedpressure, and residues are removed by azeotropic distillation togetherwith toluene. The acid chloride obtained in this way is stirred togetherwith 8.19 g (47.6 mmol) of 4-bromoaniline and 24.6 ml (190.4 mmol) ofN,N-diisopropylethylamine in 59 ml of DMF at RT for 72 h. The solvent isremoved under reduced pressure, and the crude product is purified bychromatography on silica gel 60 (mobile phase:dichloromethane→dichloromethane/methanol/triethylamine 70:30:2). Theproduct fractions are combined and concentrated in vacuo, and theresidue is dried under high vacuum. 5.5 g (37% of theory) of the titlecompound are isolated. The absolute configuration was assigned bysingle-crystal analysis of the crystal structure.

¹H-NMR (200 MHz, DMSO-d₆): δ=10.06 (s, 1H), 7.70-7.40 (m, 4H), 3.30-3.10(m, 1H), 2.94-2.45 (m, 6H), 2.15-2.04 (m, 1H), 1.73-1.45 (m, 3H),1.45-1.15 (m, 1H).

HPLC (Method 1): R₁=3.84 min.

MS (ESIpos): m/z=309 (M+H)⁺.

EXAMPLE 5A (3R)-Quinuclidine-3-carbonyl chloride hydrochloride

8.18 g (64.43 mmol) of oxalyl chloride are added dropwise to a solutionof 2.0 g (12.89 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid(Example 3A) in 10 ml of toluene. After stirring at room temperature for18 h, the reaction mixture is concentrated in vacuo and codistilled withtoluene twice. Drying under high vacuum results in 2.31 g (85.2% oftheory) of the title compound, which is reacted further without furtherpurification.

EXAMPLE 6A (3R)—N-(4′-Nitrobiphenyl-4-yl)quinuclidine-3-carboxamidehydrochloride

480 mg (3.50 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 490 mg (2.33 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 250mg (1.17 mmol) of 4-amino-4′-nitrobiphenyl in 11 ml of a 10:1 mixture ofdioxane and DMF. The reaction mixture is stirred at 100° C. for 18 h andthen concentrated. The residue is suspended in methanol and filtered.The filtration residue is washed with water, mixed with 20 ml of a 3:1mixture of acetonitrile and 1 N hydrochloric acid, again concentratedand dried under high vacuum. The above filtrate is purified bypreparative HPLC. The product fractions are concentrated, taken up in 5ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, againconcentrated and dried under high vacuum. 291 mg (61.7% of theory) ofthe title compound are obtained from the filtration residue, and afurther 65 mg (12.4% of theory) are obtained from the filtrate, in thisway.

HPLC (Method 1): R_(t)=4.13 min.

MS (ESIpos): m/z=352 (M+H)⁺.

EXAMPLE 7A (3R)—N-(4′-Aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride

A solution of 739 mg (2.10 mmol) of(3R)—N-(4′-nitrobiphenyl-4-yl)quinuclidine-3-carboxamide (Example 6A) in10 ml of methanol and 5 ml of 2 N hydrochloric acid is hydrogenatedunder atmospheric pressure in the presence of 448 mg (0.21 mmol) of 5%palladium on carbon for 2 h. Filtration through kieselgur is followed bywashing with methanol and concentration of the filtrate and drying underhigh vacuum. 755 mg (89.2% of theory) of the title compound areobtained.

HPLC (Method 1): R_(t)=3.04 min.

MS (ESIpos): m/z=322 (M+H)⁺.

EXAMPLE 8A (3R)—N-(3′-Aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride

A degassed mixture of 200 mg (0.58 mmol) of(3R)—N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide (Example4A), 215.2 mg (0.58 mmol) of 3-aminophenylboronic acid hemisulfate, 579μl (1.74 mmol) of 3 N sodium hydroxide solution and 21.2 mg (0.03 mmol)of PdCl₂(dppf) in 3 ml of DMF is heated at 90° C. for 18 h. Cooling toRT is followed by purification by preparative HPLC. The productfractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid andagain concentrated. Drying under high vacuum results in 146 mg (39.4% oftheory) of the title compound, which is reacted further without furtherpurification.

EXAMPLE 9A N-Benzyl-4′-nitrobiphenyl-4-sulfonamide

0.28 ml (2.52 mmol) of benzylamine is added to a solution of 150 mg(0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF.After 18 h at room temperature, 2.5 ml of water are added to thereaction mixture. The resulting precipitate is filtered off with suctionand dried under high vacuum. 159 mg (74.4% of theory) of the titlecompound are obtained and reacted further without further purification.

LC-MS (Method 3): R_(t)=3.83 min.; m/z=369 (M+H)⁺.

EXAMPLE 10A 4′-Amino-N-benzylbiphenyl-4-sulfonamide

416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to asolution of 136 mg (0.37 mmol) ofN-benzyl-4′-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml of DMF.After 18 h at room temperature, the reaction mixture is purified bypreparative HPLC. The product fractions are concentrated in vacuo anddried under high vacuum. 117 mg (84.3% of theory) of the title compoundare obtained.

HPLC (Method 1): R_(t)=3.91 min.

MS (ESIpos): m/z=339 (M+H)⁺.

EXAMPLE 11A N-Isopropyl-4′-nitrobiphenyl-4-sulfonamide

0.22 ml (2.52 mmol) of isopropylamine is added to a solution of 150 mg(0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF.After 18 h at room temperature, 2.5 ml of water are added to thereaction mixture. The resulting precipitate is filtered off with suctionand dried under high vacuum. 126 mg (64.4% of theory) of the titlecompound are obtained and reacted further without further purification.

LC-MS (Method 3): R_(t)=3.66 min.; m/z=321 (M+H)⁺.

EXAMPLE 12A 4′-Amino-N-isopropylbiphenyl-4-sulfonamide

288.8 mg (1.28 mmol) of tin(II) chloride dihydrate are added to asolution of 100 mg (0.26 mmol) ofN-isopropyl-4′-nitrobiphenyl-4-sulfonamide (Example 11A) in 2.0 ml ofDMF. After 18 h at room temperature, the reaction mixture is purified bypreparative HPLC. The product fractions are concentrated in vacuo anddried under high vacuum. 47 mg (63.2% of theory) of the title compoundare obtained.

HPLC (Method 1): R_(t)=3.57 min.

MS (DCI): m/z=291 (M+H)⁺.

EXEMPLARY EMBODIMENTS EXAMPLE 1[(4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino](oxo)aceticacid hydrochloride

300 mg (2.14 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 300 mg (1.43 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 180mg (0.71 mmol) of [(4′-aminobiphenyl-4-yl)amino](oxo)acetic acid [CASRegistry No. 100872-66-0] in 11 ml of a 10:1 mixture of dioxane and DMF.After 18 h at 100° C., the reaction mixture is concentrated in vacuo,and the residue is dissolved in water and acetonitrile and purified bypreparative HPLC. The concentrated product fractions are mixed with 5 mlof a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and againconcentrated. Drying under high vacuum results in 64 mg (20.3% oftheory) of the title compound.

HPLC (Method 1): R_(t)=3.40 min.

MS (ESIpos): m/z=350 (M+H)⁺.

EXAMPLE 2(3R)—N-{4′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

300 mg (2.14 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 300 mg (1.43 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 187mg (0.71 mmol) of N-(4′-aminobiphenyl-4-yl)methylsulfonamide [CASRegistry No. 82315-47-7] in 11 ml of a 10:1 mixture of dioxane and DMF.After 18 h at 100° C., the reaction mixture is concentrated in vacuo,and the residue is dissolved in water and acetonitrile and purified bypreparative HPLC. The concentrated product fractions are mixed with 5 mlof a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and againconcentrated. Drying under high vacuum results in 186 mg (58.3% oftheory) of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ=10.45 (s, 1H), 10.19 (br. s, 1H), 9.80 (s,1H), 7.71 (m, 2H), 7.61 (m, 4H), 7.28 (m, 2H), 3.60 (dd, 1H), 3.42-3.10(m, 6H), 3.01 (s, 3H), 2.45 (m, 1H), 1.93 (m, 2H), 1.76 (m, 2H).

HPLC (Method 1): R_(t)=3.59 min.

MS (ESpos): m/z=400 (M+H)⁺.

EXAMPLE 3(3R)—N-{3′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

63.6 μl (0.46 mmol) of triethylamine and 21.2 μl (0.27 mmol) ofmethanesulfonyl chloride are added to a solution of 60 mg (0.09 mmol) of(3R)—N-(3′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride(Example 8A) in 1 ml of DMF at room temperature. After 18 h at roomtemperature, the reaction mixture is diluted with a 1:1 mixture ofacetonitrile and water and purified by preparative HPLC. The productfractions are concentrated, taken up in 1 ml of 1 N hydrochloric acid,again concentrated and dried under high vacuum. 14 mg (35.2% of theory)of the title compound are obtained.

HPLC (Method 1): R_(t)=3.70 min.

LC-MS (Method 2): R_(t)=2.45 min.; m/z=400 (M+H)⁺.

EXAMPLE 4(3R)—N-{4′-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

39.1 mg (0.30 mmol) of ethanesulfonyl chloride and 84.8 μl (0.61 mmol)of triethylamine are added to a solution of 60 mg (0.15 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at roomtemperature, the reaction mixture is purified by preparative HPLC. Theproduct fractions are concentrated, mixed with 2 ml of a 1:1 mixture ofacetonitrile and 1 N hydrochloric acid, again concentrated and driedunder high vacuum. 26 mg (35.2% of theory) of the title compound areobtained.

HPLC (Method 1): R_(t)=3.71 min.

MS (ESIpos): m/z=414 (M+H)⁺.

EXAMPLE 5(3R)—N-{4′-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

A solution of 80 mg (0.20 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 71.7 mg (0.41 mmol) of phenylsulfonylchloride in 1.0 ml of pyridine is stirred at room temperature for 18 h.The reaction mixture is concentrated in vacuo and the residue ispurified by preparative HPLC. The product fractions are concentrated,mixed with 3 ml of 1 N hydrochloric acid, again concentrated and driedunder high vacuum. 52 mg (51.5% of theory) of the title compound areobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=10.40 (s, 1H), 10.37 (s, 1H), 9.85 (br. s,1H), 7.80 (m, 2H), 7.66 (m, 2H), 7.63-7.49 (m, 7H), 7.17 (m, 2H), 3.61(dd, 1H), 3.43-3.17 (m, 5H), 3.11 (m, 1H), 2.41 (m, 1H), 1.92 (m, 2H),1.73 (m, 2H).

HPLC (Method 1): R_(t)=4.05 min.

MS (ESIpos): m/z=462 (M+H)⁺.

EXAMPLE 6(3R)—N-{4′-[(Benzylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide

A solution of 80 mg (0.20 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 77.4 mg (0.41 mmol) ofphenylmethanesulfonyl chloride in 1.0 ml of pyridine is stirred at roomtemperature for 18 h. The reaction mixture is concentrated in vacuo andthe residue is purified by preparative HPLC. The product fractions areconcentrated, mixed with 3 ml of 1 N hydrochloric acid, againconcentrated and dried under high vacuum. 34 mg (32.7% of theory) of thetitle compound are obtained.

HPLC (Method 1): R_(t)=4.12 min.

MS (ESIpos): m/z=476 (M+H)⁺.

EXAMPLE 7(3R)—N-[4′-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamidehydrochloride

213.5 mg (1.54 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 216.3 mg (1.03 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and127.8 mg (0.51 mmol) of (4′-amino-4-biphenyl)sulfonamide in 5.5 ml of a10:1 mixture of dioxane and DMF. After 18 h at 100° C., a further 216.3mg (1.03 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochlorideare added. After a further 18 h at 100° C., the product is precipitatedby adding acetonitrile/water (2:1). Drying under high vacuum results in148 mg (71.9% of theory) of the title compound.

¹H-NMR (200 MHz, DMSO-d₆): δ=10.06 (s, 1H), 7.92-7.80 (m, 4H), 7.79-7.68(m, 4H), 7.39 (s, 2H), 3.22 (dd, 1H), 2.93-2.58 (m, 6H), 2.09 (m, 1H),1.60 (m, 3H), 1.33 (m, 1H).

HPLC (Method 1): R_(t)=3.40 min.

MS (ESIpos): m/z=386 (M+H)⁺.

EXAMPLE 8(3R)—N-(4′-[(Isopropylamino)sulfonyl]biphenyl-4-yl)quinuclidine-3-carboxamidehydrochloride

64.3 mg (0.46 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 65.1 mg (0.31 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and45.0 mg (0.15 mmol) of 4′-amino-N-isopropylbiphenyl-4-sulfonamide(Example 12A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 hat 100° C., the reaction mixture is concentrated in vacuo. The residueis dissolved in water and acetonitrile and purified by preparative HPLC.The product fractions are concentrated, mixed with 5 ml of a 2:1 mixtureof acetonitrile and 1 N hydrochloric acid, again concentrated and driedunder high vacuum. 21 mg (29.2% of theory) of the title compound areobtained.

HPLC (Method 1): R_(t)=3.93 min.

MS (ESIpos): m/z=428 (M+H)⁺.

EXAMPLE 9(3R)—N-{4′-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

73.5 mg (0.60 mmol) of potassium carbonate are added to a mixture,prepared under argon, of 74.5 mg (0.35 mmol) of(3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 60mg (0.18 mmol) of 4′-amino-N-benzylbiphenyl-4-sulfonamide (Example 10A)in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., afurther 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloridehydrochloride are added. After a further 24 h at 100° C., the reactionmixture is concentrated in vacuo. The residue is dissolved in water andacetonitrile and purified by preparative HPLC. The product fractions areconcentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 Nhydrochloric acid, again concentrated and dried under high vacuum. 64 mg(70.5% of theory) of the title compound are obtained.

HPLC (Method 1): R_(t)=4.17 min.

MS (ESIpos): m/z=476 (M+H)⁺.

EXAMPLE 10(3R)—N-(4′-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide

17.4 mg (0.30 mmol) of methyl isocyanate and 84.8 μl (0.61 mmol) oftriethylamine are added to a solution of 60 mg (0.15 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at roomtemperature, 5 ml of water are added to the reaction mixture. Theresulting precipitate is filtered off with suction, washed with waterand dried under high vacuum. 47 mg (73.5% of theory) of the titlecompound are obtained.

HPLC (Method 1): R_(t)=3.44 min.

MS (ESIpos): m/z=379 (M+H)⁺.

EXAMPLE 11(3R)—N-(4′-{([(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamidehydrochloride

33.8 mg (0.30 mmol) of cyclopentyl isocyanate and 84.8 μl (0.61 mmol) oftriethylamine are added to a solution of 60 mg (0.15 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at roomtemperature, 5 ml of water are added to the reaction mixture. Theresulting precipitate is filtered off with suction, washed with waterand dried under high vacuum. A preparative HPLC is carried out forfurther purification. The product fractions are concentrated, mixed with3 ml of 1 N hydrochloric acid, again concentrated and dried under highvacuum. 28 mg (39.2% of theory) of the title compound are obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=10.33 (s, 1H), 9.95 (s, 1H), 8.51 (s, 1H),7.67 (m, 2H), 7.58 (m, 2H), 7.50 (m, 2H), 7.44 (m, 2H), 6.29 (br. S,1H), 3.96 (m, 1H), 3.60 (m, 1H), 3.37 (m, 1H), 3.29-3.08 (m, 5H), 2.43(m, 1H), 1.92 (m, 2H), 1.84 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H), 1.55(m, 2H), 1.38 (m, 2H).

HPLC (Method 1): R_(t)=4.05 min.

MS (ESIpos): m/z=433 (M+H)⁺.

EXAMPLE 12(3R)—N-(4′-{([(Ethylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide

21.6 mg (0.30 mmol) of ethyl isocyanate and 84.8 μl (0.61 mmol) oftriethylamine are added to a solution of 60 mg (0.15 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at roomtemperature, 5 ml of water are added to the reaction mixture. Theresulting precipitate is filtered off with suction, washed with waterand dried under high vacuum. 57 mg (88.0% of theory) of the titlecompound are obtained.

HPLC (Method 1): R_(t)=3.62 min.

MS (ESIpos): m/z=393 (M+H)⁺.

EXAMPLE 13(3R)—N-[4′-({[(3-Methoxyphenyl)amino]carbonyl}amino)biphenyl-4-yl]quinuclidine-3-carboxamidehydrochloride

45.4 mg (0.30 mmol) of 3-methoxyphenyl isocyanate and 84.8 μl (0.61mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at roomtemperature, 5 ml of water are added to the reaction mixture. Theresulting precipitate is filtered off with suction, washed with waterand dried under high vacuum. A preparative HPLC is carried out forfurther purification. The product fractions are concentrated, mixed with3 ml of 1 N hydrochloric acid, again concentrated and dried under highvacuum. 22 mg (27.6% of theory) of the title compound are obtained.

HPLC (Method 1): R_(t)=4.19 min.

MS (ESIpos): m/z=471 (M+H)⁺.

EXAMPLE 14(3R)—N-{4′-[(3-Chlorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

A solution of 50 mg (0.13 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 44.4 mg (0.25 mmol) of 3-chlorobenzoylchloride in 1.0 ml of pyridine is stirred at room temperature for 3 h.The reaction mixture is concentrated in vacuo, and the residue ispurified by preparative HPLC. The product fractions are concentrated,mixed with 3 ml of 1 N hydrochloric acid, again concentrated and driedunder high vacuum. 62 mg (98.5% of theory) of the title compound areobtained.

HPLC (Method 1): R_(t)=4.41 min.

MS (ESIpos): m/z=460 (M+H)⁺.

EXAMPLE 15(3R)—N-{4′-[(3-Fluorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

A solution of 50 mg (0.13 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 40.2 mg (0.25 mmol) of 3-fluorobenzoylchloride in 1.0 ml of pyridine is stirred at room temperature for 3 h.The reaction mixture is concentrated in vacuo, and the residue ispurified by preparative HPLC. The product fractions are concentrated,mixed with 3 ml of 1 N hydrochloric acid, again concentrated and driedunder high vacuum. 48 mg (73.4% of theory) of the title compound areobtained.

¹H-NMR (200 MHz, DMSO-d₆): δ=10.48 (s, 1H), 10.43 (s, 1H), 10.21 (br. s,1H), 7.92-7.80 (m, 3H), 7.79-7.57 (m, 8H), 7.49 (m, 1H), 3.61 (m, 1H),3.44-3.08 (m, 6H), 2.46 (m, 1H), 1.92 (m, 2H), 1.75 (m, 2H).

HPLC (Method 1): R_(t)=4.21 min.

MS (ESIpos): m/z=444 (M+H)⁺.

EXAMPLE 16(3R)—N-{4′-[(2-Methoxyacetyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

A solution of 50 mg (0.13 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetylchloride in 1.0 ml of pyridine is stirred at room temperature for 18 h.The reaction mixture is mixed with 3 ml of DMSO and purified bypreparative HPLC. The product fractions are concentrated, mixed with 5ml of 1 N hydrochloric acid, again concentrated and dried under highvacuum. 16 mg (29.4% of theory) of the title compound are obtained.

HPLC (Method 1): R_(t)=3.63 min.

MS (ESIpos): m/z=394 (M+H)⁺.

EXAMPLE 17(3R)—N-{4′-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride

A solution of 50 mg (0.13 mmol) of((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamidedihydrochloride (Example 7A) and 38.5 μl (0.32 mmol) ofcyclopentanecarbonyl chloride in 1.0 ml of pyridine is stirred at roomtemperature for 18 h. The reaction mixture is mixed with 3 ml of DMSOand purified by preparative HPLC. The product fractions areconcentrated, mixed with 5 ml of 1 N hydrochloric acid, againconcentrated and dried under high vacuum. 22 mg (38.2% of theory) of thetitle compound are obtained.

HPLC (Method 1): R_(t)=4.18 min.

MS (ESIpos): m/z=418 (M+H)⁺.

The invention claimed is:
 1. A method for treating cognitive impairmentin a patient suffering from Alzheimer's disease or schizophreniacomprising administering to the subject a pharmaceutical compositioncomprising: i) a compound represented by Formula (I):

 in a pharmaceutically effective amount, in which R¹ is a group of theformula —NR²—CO—NR³R⁴, —NR²—CO—CO—OR⁵, —NH—SO ₂R⁶, —SO₂NHR⁷ or—NH—CO—R⁸, where R² is hydrogen or C₁-C₆-alkyl, R³ and R⁴ areindependently of one another hydrogen, C_(a)-C₆-alkyl, C₃-C₈-cycloalkylor phenyl, which is optionally substituted by up to 3 radicalsindependently of one another selected from the group of halogen, cyano,C₁-C₆-alkyl, C₁-C₆-alkoxy, trifluoromethyl and trifluoromethoxy, or R³and R⁴ together with the nitrogen atom to which they are bonded form a5- to 6-membered heterocyclyl, R⁵ is hydrogen, C₁-C₆-alkyl,C₃-C₈-cycloalkyl or aryl, where C₁-C₆-alkyl is optionally substituted byaryl, R⁶ is C₁-C₆-alkyl, C₃-C₈-cycloalkyl, 5- to 6-memberedheterocyclyl, aryl or 5- to 6-membered heteroaryl, where C₁-C₆-alkyl isoptionally substituted by aryl, R⁷ is hydrogen, C₁-C₆-alkyl,C₃-C₈-cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to6-membered heteroaryl, where C₁-C₆-alkyl is optionally substituted byaryl, R⁸ is C₃-C₈-cycloalkyl, C₁-C₆-alkyl or phenyl, where C₁-C₆-alkylis substituted by C₁-C₆-alkoxy and phenyl by 1 to 3 radicalsindependently of one another selected from the group of halogen, cyano,C₁-C₆-alkyl, C₁-C₆-alkoxy, trifluoromethyl and trifluoromethoxy, or asalt thereof; and ii) a pharmaceutically acceptable carrier.
 2. Themethod of claim 1, further comprising co-administering a second activeingredient for the treatment of the cognitive impairment.
 3. The methodof claim 1, wherein the administering is by an oral, transdermal,parenteral or inhalation route.
 4. The method of claim 1, wherein thecognitive impairment is Alzheimer's disease.
 5. The method of claim 4,wherein the amount of the compound represented by Formula (I) iseffective to stimulate an alpha7 nicotinic acetylcholine receptor (α7nAChR).
 6. The method of claim 4, further comprising co-administering asecond active ingredient for the treatment of Alzheimer's disease. 7.The method of claim 4, wherein the administering is by an oral,transdermal, parenteral or inhalation route.
 8. The method of claim 1,wherein the cognitive impairment is schizophrenia.
 9. The method ofclaim 8, wherein the amount of the compound represented by Formula (I)is effective to stimulate an alpha7 nicotinic acetylcholine receptor (α7nAChR).
 10. The method of claim 8, further comprising co-administering asecond active ingredient for the treatment of schizophrenia.
 11. Themethod of claim 8, wherein the administration is by an oral,transdermal, parenteral or inhalation route.
 12. A compound, or a saltthereof, selected from the group consisting of: [(4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino]-(oxo)acetic acidhydrochloride;(3R)-N-{4′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;(3R)-N-{3′-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;(3R)-N-{4′-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;(3R)-N-{4′-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;(3R)-N-{4′-[(Benzylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide;(3R)-N-[4′-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamidehydrochloride;(3R)-N-(4′-[(Isopropylamino)sulfonyl]biphenyl-4-yl)quinuclidine-3-carboxamidehydrochloride;(3R)-N-{4′-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride;(3R)-N-(4′-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide;(3R)-N-(4′-{([(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamidehydrochloride;(3R)-N-(4′-{([(Ethylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide;(3R)-N-[4′-({[(3-Methoxyphenyl)amino]carbonyl}amino)biphenyl-4-yl]quinuclidine-3-carboxamidehydrochloride;(3R)-N-{4′-[(3-Chlorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride;(3R)-N-{4′-[(3-Fluorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride;(3R)-N-{4′-[(2-Methoxyacetyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride; and(3R)-N-{4′-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamidehydrochloride.
 13. A method of treating a cognitive impairment in apatient suffering from Alzheimer's disease or schizophrenia, comprisingadministering to the patient a compound according to claim
 12. 14. Themethod of claim 13, wherein the cognitive impairment is Alzheimer'sdisease.
 15. The method of claim 13, wherein the cognitive impairment isschizophrenia.
 16. The method of claim 13, further comprisingco-administering a second active ingredient for the treatment of thecognitive impairment.
 17. The method of claim 13, wherein theadministering is by an oral, transdermal, parenteral or inhalationroute.
 18. A pharmaceutical composition comprising a compound accordingto claim 12 and a pharmaceutically acceptable carrier.
 19. A method oftreating a cognitive impairment in a patient suffering from Alzheimer'sdisease or schizophrenia, comprising administering to the patient apharmaceutical composition according to claim
 18. 20. The method ofclaim 19, wherein the cognitive impairment is Alzheimer's disease. 21.The method of claim 19, wherein the cognitive impairment isschizophrenia.
 22. The method of claim 19, further comprisingco-administering a second active ingredient for the treatment of thecognitive impairment.
 23. The method of claim 19, wherein theadministering is by an oral, transdermal, parenteral or inhalationroute.